This proposal is in response to a request for application (RFA) from the NIH to study chronic wounds. Chronic wounds are observed in millions of Americans with abnormalities of their sensory nervous system due to diabetes mellitus, spinal cord injury, peripheral vascular disease, and aging. We propose the novel concept that the frequency of chronic wounds in this population is not merely related to undetected trauma in denervated skin, but rather a reduction or absence of neuropeptides which are essential for normal tissue repair. Tissue repair is known to be abnormal in these populations resulting in morbidity, mortality, time loss from work, countless days of hospitalization or institutionalization and millions of dollars in health care costs. In this application we will test the hypotheses that: (1) An intact sensory nervous system is essential for normal cutaneous wound healing (2) chronic-wound development in neurologically impaired patients are the result of defects in acute wound healing, (3) neurologically impaired skin is characterized by abnormalities in the expression of substance P (SP), receptor (SPR), neutral endopeptidase (NEP), nerve growth factor (NGF) and/or NGF receptor (NGFR), and (4) deficits in skin integrity and wound healing can be overcome by therapeutic replacement or modulation of components of a defective cutaneous sensory nervous system. These hypotheses will be tested by the following Specific Aims: Specific Aim #1: To examine the expression and regulation of cutaneous SP, SPR, and NEP in the skin of normal and neurologically compromised patients; Specific Aim #2: To examine the expression and regulation of cutaneous NGF and NGFR in the skin of normal and neurologically compromised patients; Specific Aim #3: To examine the role of the neurological system in skin integrity and wound healing in neurologically impaired murine models and; Specific Aim #4 to determine if skin integrity and wound healing in neurologically impaired animals can be augmented by the modulation of cutaneous neurological system. These peptides will be localized in the skin by in situ hybridization and/or immunohistochemistry and quantitated by RNAse protection assay, Northern blot, RIA, ELISA, and/or bioassay. Our proposed studies may lead to novel therapeutic approaches for the treatment of poor skin integrity and chronic wounds in patients with diabetes and/or neurologic deficits and skin-prosthetic interactions. The research will be carried out by three groups of investigators who have ongoing collaborations. The San Francisco group provides expertise in neuropeptides with well characterized reagents. The Seattle group provides wound healing expertise with a well characterized human wound tissue library and access to patients with chronic non-healing ulcers and the Portland group provides expertise in cutaneous inflammation including the role of neuropeptides in cutaneous inflammation.